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Topoisomerase II-DNA complexes trapped by ICRF-193 perturb chromatin structure

Thomas Germe1, Olivier Hyrien

  • 1Laboratoire de Génétique Moléculaire, Ecole Normale Supérieure, Paris, France.

EMBO Reports
|July 19, 2005
PubMed

Insights

DNA topoisomerase II (topo II) inhibitors like ICRF-193 disrupt nucleosome spacing by trapping DNA-bound clamps, not by increasing DNA catenation. This chromatin perturbation impacts cellular effects.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • DNA topoisomerase II (topo II) is crucial for DNA replication and chromosome organization.
  • Topo II is a validated target for anticancer therapies.
  • Inhibiting topo II can lead to DNA catenation and potentially disrupt chromatin assembly.

Purpose of the Study:

  • To investigate the effects of the topo II inhibitor ICRF-193 on nucleosome deposition and spacing.
  • To determine whether DNA catenation or trapped topo II clamps are responsible for chromatin perturbation.

Main Methods:

  • Experiments were conducted using Xenopus egg extracts.
  • Nucleosome deposition and spacing were analyzed following treatment with the topo II inhibitor ICRF-193.
  • The roles of DNA decatenation and trapped topo II clamps were assessed.

Main Results:

  • ICRF-193 treatment did not inhibit bulk nucleosome deposition.
  • Nucleosome spacing was perturbed by ICRF-193, attributed to trapped topo II-closed clamps.
  • Inhibition of DNA decatenation alone had minimal impact on nucleosome deposition and spacing.

Conclusions:

  • Topo II clamps, rather than DNA catenation, are the primary cause of chromatin perturbation by ICRF-193.
  • DNA can accommodate nucleosomes and catenane nodes simultaneously.
  • Chromatin perturbation by topo II clamps may underlie the cellular effects of ICRF-193.

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